This review aims to evaluate the efficacy of alpha-lipoic acid (ALA) in combating toxic elements, such as aluminum, arsenic, lead, mercury, and cadmium. The primary research question addressed is whether ALA can effectively mitigate the toxic effects of these metals through its antioxidant and chelating properties. Articles published between 1995 and 2024 were collected from Scopus, PubMed, Google Scholar, and Web of Science. Using Boolean (AND and OR), English-language publications were selected based on medical subject headings, titles, or abstracts that contained keywords related to ALA, metals, toxicity, antioxidants, and chelation. ALA supplementation significantly enhances cellular defense mechanisms and antioxidant enzyme activity. It effectively mitigates the adverse effects of aluminum exposure, counters arsenic toxicity in various cells and organs, and reduces cadmium toxicity, resulting in lower mortality rates among treated groups. Although ALA acts as a lead chelator, its efficacy is less than standard chelators. In the case of mercury, ALA shows beneficial effects in long-term therapy, although its capacity to reduce mercury concentration is limited. Overall, ALA emerges as a promising alternative for alleviating metal toxicity by enhancing antioxidant defenses, chelating toxic metals, and reversing their harmful effects. Further research in this area is encouraged to explore the full potential of ALA in mitigating the toxic effects of metals on biological systems.

Alpha-lipoic acid (ALA) is a naturally occurring compound synthesized by mitochondria and widely distributed in both animal and plant tissues. It primarily influences cellular metabolism and oxidative stress networks through its antioxidant properties and is an important drug for treating metabolic diseases associated with oxidative damage. Nevertheless, research indicates that the mechanism by which ALA affects cancer cells is distinct from that observed in normal cells, exhibiting pro-oxidative properties. Therefore, this review aims to describe the main chemical and biological functions of ALA in the cancer environment, including its mechanisms and effects in tumor prevention and anticancer activity, as well as its role as an adjunctive drug in cancer therapy. We specifically focus on the interactions between ALA and various carcinogenic and anti-carcinogenic pathways and discuss ALA's pro-oxidative capabilities in the unique redox environment of cancer cells. Additionally, we elaborate on ALA's roles in nanomedicine, hypoxia-inducible factors, and cancer stem cell research, proposing hypotheses and potential explanations for currently unresolved issues.

Arsenic (As) is a toxic metalloid that affects many organs through drinking water. This study aims to examine the efficacy of ozone therapy on chronic arsenic toxicity. Twenty-four male Wistar albino rats were housed in individual cages and grouped as control, As, O₃, and As + O_3. As was applied by adding 5 mg/kg/day in drinking water for 60 days. Ozone therapy was applied at 0.5 mg/kg/day (i.p.) O₃ in the last 5 days of the experimental period. Tissues were harvested and analyzed for histopathological injury and apoptotic markers. There was no significant difference between the As + O₃ and O₃ groups (p = 0.186 and p = 0.599) for light microscopic criteria: inflammatory cell infiltration and hydropic degeneration in liver tissue.In TUNEL assessments, similar outcomes were obtained in the control and As + O₃ groups. A statistically significant increase was observed in p53 and Caspase 3 (Casp-3) expression levels in the As group compared to the O₃ and As + O₃ groups. There was no significant difference between the As + O₃ and O₃ groups on peritubular hemorrhage and desquamation parameters in kidneys (p = 0.147 and p = 0.094). The KIM-1 expression level was significantly increased in the As group compared to the As + O₃ group (p = 0.01), and the Casp-3 expression level was not significantly changed in the O₃ group compared to the As + O₃ group (p = 0.59). In conclusion, it is determined that ozone therapy has ameliorative effects on the microscopic injury of liver and kidney tissues. In addition to microscopic improvement, KIM-1 gene expression levels were ameliorated in the kidneys. The apoptotic cell counts and the Casp-3 and p53 gene expression levels were decreased by O₃ administration. Thus, ozone therapy can be a treatment choice for As toxicity.

The chronic kidney disease of unknown etiology (CKDu) is a global health concern primarily impacting tropical farming communities. Although the precise etiology is debated, CKDu is associated with environmental exposures including heat stress and chemical contaminants such as fluoride, heavy metals, and herbicide glyphosate. However, a comprehensive synthesis is lacking on molecular networks underpinning renal damage induced by these factors. Addressing this gap, here we present key molecular events associated with heat and chemical exposures. We identified that caspase activation and lipid peroxidation are common endpoints of glyphosate exposure, while vasopressin and polyol pathways are associated with heat stress and dehydration. Heavy metal exposure is shown to induce lipid peroxidation and endoplasmic reticulum stress from ROS activated MAPK, NFĸB, and caspase. Collectively, we identify that environmental exposure induced increased cellular oxidative stress as a common mechanism mediating renal cell inflammation, apoptosis, and necrosis, likely contributing to CKDu initiation and progression.

Arsenic is a natural element which exists in the environment in inorganic and organic forms. In humans, the main reason for the toxicity of arsenic is its uptake via water sources. As polluted water and the problems associated with it can be found in many countries. Therefore, considering all these positive effects of melatonin, this review is aimed at melatonin supplementation therapy on arsenic toxicity which seems to be a suitable therapeutic agent to eliminate the adverse effects of arsenic.

It is seen in previous studies that chronic exposure to arsenic could cause serious dys functions of organs and induce different degrees of toxicities that is one of the first hazardous materials in the classification of substances by the United States Environmental Protection Agency so leads to costly cleanup operations burdening the economy. Arsenic harmfulness degree depends on the bioavailability, chemical form, valence state, detoxification, and metabolism of human body. The oxidative stress has a major role in arsenic-induced toxicity; on the other hand, it was discovered that melatonin is a powerful scavenger for free radical and it's an extensive-spectrum antioxidant.

Due to its highly lipophilic and small size properties, melatonin accesses all intracellular organs by easily passing via the cell membrane and prevents protein, DNA damage, and lipid peroxidation. In particular, melatonin, by protecting and reducing oxidative stress in mitochondria, can normalize homeostasis and mitochondrial function and ultimately prevent apoptosis and cell death.

Arsenic and fluoride are recognized globally as the most serious inorganic contaminants in drinking water. As there is no safe and effective treatment for the cases of fluoride poisoning and combined arsenic-fluoride toxicity, the present study was planned to assess (i) the mechanism of combined exposure to arsenic and fluoride via biochemical and spectroscopic data; (ii) the effect of a thiol chelating agent, meso-2,3-dimercaptosuccinic acid (DMSA), either individually or in combination with the antioxidant vitamin C in reversing arsenic-fluoride toxicity; and (iii) whether combination therapy enhances arsenic and fluoride removal from blood and soft tissues.

Rats were exposed to arsenic (50 mg l-1) and fluoride (50 mg l-1) individually and in combination for 9 months and later administered DMSA (50 mg kg-1) via an i.p. route and vitamin C (25 mg kg-1) orally for 5 days. Biochemical parameters suggestive of alterations in the heme synthesis pathway, oxidative stress in blood, the liver and the kidneys, and concentrations of arsenic and fluoride in blood and soft tissues were studied. We also studied the infrared (IR) spectra of DNA extracted from the livers and kidneys of the normal and exposed animals.

It was found that chronic arsenic and fluoride exposure led to an increased oxidative stress condition and impaired heme synthesis (67% inhibition in δ-aminolevulinic acid dehydratase activity and 38% increase in δ-aminolevulinic acid synthetase activity). The decreased antioxidant defense mechanism was marked by a 2.25 fold increased concentration of Reactive Oxygen Species (ROS) and a 28% decrease in the Glutathione (GSH) level. Interestingly, concomitant exposure to arsenic and fluoride did not lead to antagonistic effects as the toxic effects were the same as those seen during the individual exposure to both the toxicants. It suggests that toxicity depends on the dose and duration of exposure. Combination therapy with DMSA and vitamin C showed a better efficacy than monotherapy in terms of reducing the arsenic and fluoride burden (more than 70% in blood and soft tissues) as well as reversal in the altered biochemical variables indicative of oxidative stress and tissue damage (80-85%). The infrared (IR) spectra of DNA isolated from the liver and kidneys suggested that the treatment with vitamin C and DMSA had no beneficial effects in terms of reversing DNA damage.

On the basis of the above observations, we suggest that the combinational therapy of DMSA and vitamin C would be more effective in arsenic and/or fluoride toxicity; however, more detailed studies are required to address recoveries in DNA damage.

The industrial and technological advancements in the world have also contributed to the rapid deterioration in the environment quality through introduction of obnoxious pollutants that threaten to destroy the subtle balance in the ecosystem. The environment contaminants cause severe adverse effects to humans, flora and fauna that are mostly irreversible. Chief among these toxicants is arsenic, a metalloid, which is considered among the most dangerous environmental toxins that leads to various diseases which affect the quality of life even when present in small quantities. Treatment of arsenic-mediated disorders still remains a challenge due to lack of effective options. Chelation therapy has been the most widely used method to detoxify arsenic. But this method is associated with deleterious effects leading various toxicities such as hepatotoxicity, neurotoxicity and other adverse effects. It has been discovered that indigenous drugs of plant origin display effective and progressive relief from arsenic-mediated toxicity without any side-effects. Further, these phytochemicals have also been found to aid the elimination of arsenic from the biological system and therefore can be more effective than conventional therapeutic agents in ameliorating arsenic-mediated toxicity. This review presents an overview of the toxic effects of arsenic and the therapeutic strategies that are available to mitigate the toxic effects with emphasis on chelation as well as protective and detoxifying activities of different phytochemicals and herbal drugs against arsenic. This information may serve as a primer in identifying novel prophylactic as well as therapeutic formulations against arsenic-induced toxicity.

Environmental exposure to arsenic represents a serious challenge to humans and other animals. The aim of the present study was to test the protective effect of antioxidant N-acetylcysteine (NAC) either individually or in combination with a chelating agent, meso-2,3-dimercaptosuccinic acid (DMSA), against sodium arsenite oral toxicity in male rats. Five groups were used: control; arsenic group (orally administrated in a concentration of 2 mg/kg body weight [b.w.]); the other three groups were orally administrated sodium arsenite in a concentration of 2 mg/kg b.w. followed by either NAC (10 mg/kg b.w., intraperitoneally [i.p.]), DMSA (50 mg/kg b.w., i.p.) or NAC plus DMSA. Arsenic toxicity caused significant rise in serum aspartate aminotransferase, alanine aminotransferase and total bilirubin, and a significant decrease in total protein (TP) and albumin levels after 3 weeks of experimental period. In addition, arsenic-treated rats showed significantly higher arsenic content in liver and significant rise in hepatic malondialdehyde level. By contrast, sharp decreases in glutathione content and catalase and glutathione reductase activities were discernible. NAC and/or DMSA counteracted most of these physiologic and biochemical defects. NAC monotherapy was more effective than DMSA in increasing TP, while DMSA was more effective in decreasing alanine aminotransferase. The combined treatment was superior over monotherapies in recovery of TP and glutathione. Biochemical data were well supported by histopathological and ultrastructural findings. In conclusion, the combination therapy of NAC and DMSA may be an ideal choice against oxidative insult induced by arsenic poisoning.

Arsenic (As) is ubiquitous in nature and humans being exposed to arsenic via atmospheric air, ground water and food sources are certain. Major sources of arsenic contamination could be either through geological or via anthropogenic activities. In physiological individuals, organ system is described as group of organs that transact collectively and associate with other systems for conventional body functions. Arsenic has been associated with persuading a variety of complications in body organ systems: integumentary, nervous, respiratory, cardiovascular, hematopoietic, immune, endocrine, hepatic, renal, reproductive system and development. In this review, we outline the effects of arsenic on the human body with a main focus on assorted organ systems with respective disease conditions. Additionally, underlying mechanisms of disease development in each organ system due to arsenic have also been explored. Strikingly, arsenic has been able to induce epigenetic changes (in utero) and genetic mutations (a leading cause of cancer) in the body. Occurrence of various arsenic induced health effects involving emerging areas such as epigenetics and cancer along with their respective mechanisms are also briefly discussed.

Arsenic is an environmental pollutant and its contamination in drinking water poses serious world wide environmental health threats. It produces multiple adverse effects in various tissues, including the kidney. However, biochemical mechanism and renal response to its toxic insult are not completely elucidated. We hypothesized that sodium arsenate (ARS) induces oxidative stress and alters the structure and metabolic functions of kidney. Male Wistar rats were administered ARS (10 mg/kg body weight/day), intraperitoneally daily for 10 days. ARS administration increased blood urea nitrogen, serum creatinine, cholesterol, glucose, and phospholipids but decreased inorganic phosphate, indicating kidney toxicity. The activity of brush border membrane (BBM) enzymes significantly lowered in both cortex and medulla. Activity of hexokinase, lactate dehydrogenase, glucose-6-phosphate dehydrogenases, and NADP-malic enzyme significantly increased whereas malate dehydrogenase, glucose-6-phosphatase, and fructose 1,6 bis phosphatase decreased by ARS exposure. The activity of superoxide dismutase, GSH-peroxidase, and catalase were selectively altered in renal tissues along with an increase in lipid peroxidation. The present results indicated that ARS induced oxidative stress caused severe renal damage that resulted in altered levels of carbohydrate metabolism and BBM enzymes.

Chronic exposure to arsenic in drinking water is associated with skin lesions, neurological effects, hypertension and high risk of cancer. The treatment in use at present employs administration of thiol chelators, such as meso-2,3-dimercaptosuccinic acid (DMSA) which are compromised with number of limitations due to their lipophobic nature. To address this problem, therapeutic efficacy of monoisoamyl meso-2,3-dimercaptosuccinic acid (MiADMSA), an analog of DMSA having lipophilic character, was examined against chronic arsenic poisoning in rats. Adult male Wistar rats were orally exposed to arsenic (2mg sodium arsenite/kg body weight) for 10 weeks followed by treatment with MiADMSA (50mg/kg, orally, once daily for 5 consecutive days). As-exposed rats showed significant differences in behavioral functions (open field behavior, total locomotor activity, grip strength and exploratory behavior) and water maze learning. Further, the biochemical studies performed on three brain regions (cerebellum, cortex and hippocampus) also showed significant elevation in malondialdehyde (MDA) levels with a concomitant decrease in the oxidative stress marker enzymes Mn-superoxide dismutase (Mn-SOD), Cu/Zn-superoxide dismutase (Cu/Zn-SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione-S-transferase (GST). The alterations were more pronounced in cortex compared to cerebellum and hippocampus. The results showed that MiADMSA significantly reversed the As-induced alterations in behavior and biochemical variables suggestive of oxidative injury.

The aim of the present study was to investigate the protective effect of conjugated linolenic acid (CLnA), present in vegetable oils against arsenite-induced renal oxidative stress.

Albino rats were divided into six groups. Group 1 was control and group 2 was treated with sodium arsenite (Sa; 10 mg/kg BW). Rats in groups 3 and 4 were treated with mixture of α-eleostearic acid and punicic acid (1:1) (0.5% and 1.0%, respectively), whereas rats in the groups 5 and 6 were treated with 0.5% of α-eleostearic acid and 0.5% of punicic acid, respectively, along with Sa by oral gavage once daily.

Results revealed that activity of antioxidant enzymes and total reduced glutathione content, total protein content, and phospholipid content in kidney were decreased significantly in arsenite-treated group compared with control. Activity of nitric oxide synthase, peroxidation of lipid, protein oxidation, total cholesterol content, total lipid content of kidney, and plasma creatinine level were increased significantly (P < 0.05) in arsenite-treated rats compared with control. Fatty-acid composition of renal lipids showed significant decrease in monounsaturated fatty acid, polyunsaturated fatty acid (PUFA) content, and increase in saturated fatty acid content due to oxidative stress. PUFA such as γ-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid decreased significantly with significant (P < 0.05) increase in arachidonic acid content after Sa treatment. Administration of blended product of both the isomers caused better restoration of renal fatty acids and other altered parameters.

CLnA isomers caused amelioration of renal oxidative stress and the isomers showed synergistic activity.

Arsenic is an environmental pollutant and its contamination in the drinking water is considered as a serious worldwide environmental health threat. The chronic arsenic exposure is a cause of immense health distress as it accounts for the increased risk of various disorders such as cardiovascular abnormalities, diabetes mellitus, neurotoxicity, and nephrotoxicity. In addition, the exposure to arsenic has been suggested to affect the liver function and to induce hepatotoxicity. Moreover, few studies demonstrated the induction of carcinogenicity especially cancer of the skin, bladder, and lungs after the chronic exposure to arsenic. The present review addresses diverse mechanisms involved in the pathogenesis of arsenic-induced toxicity and end-organ damage.

α-Lipoic acid (ALA) has been termed the 'ideal' antioxidant, a readily absorbed and bioavailable compound capable of scavenging a number of free radicals, and it has been used for treating diseases in which oxidative stress plays a major role. The present study was designed to gain a better understanding for the positive effects of ALA on the models of acute and chronic inflammation in rats, and also determine its anti-oxidative potency. In an acute model, three doses of ALA (50, 100 and 200 mg/kg) and one dose of indomethacin (25 mg/kg) or diclofenac (25 mg/kg) were administered to rats by oral administration. The paw volumes of the animals were calculated plethysmometrically, and 0·1 ml of 1 % carrageenan (CAR) was injected into the hind paw of each animal 1 h after oral drug administration. The change in paw volume was detected as five replicates every 60 min by plethysmometry. In particular, we investigated the activities of catalase, superoxide dismutase (SOD), glutathione S-transferase (GST), glutathione peroxidase (GPx), glutathione reductase (GR), inducible NO synthase (iNOS) and myeloperoxidase (MPx), and the amounts of lipid peroxidation (LPO) or total GSH in the paw tissues of CAR-injected rats. We showed that ALA exhibited anti-inflammatory effects on both acute and chronic inflammations, and a strongly anti-oxidative potency on linoleic acid oxidation. Moreover, the administration of CAR induced oedema in the paws. ALA significantly inhibited the ability of CAR to induce: (1) the degree of acute inflammation, (2) the rise in MPx activity, (3) the increases of GST and iNOS activities and the amount of LPO and (4) the decreases of GPx, GR and SOD activities and the amount of GSH. In conclusion, these results suggest that the anti-inflammatory properties of ALA, which has a strong anti-oxidative potency, could be related to its positive effects on the antioxidant system in a variety of tissues in rats.

Cadmium (Cd) is a heavy metal which causes concern as an environmental toxicant. Therapy with chelating agents is considered to be the rational treatment against metal poisoning. This study was designed to evaluate whether meso-2,3-dimercaptosuccinic acid (DMSA) could alleviate oxidative stress and vascular dysfunction in mice with subchronic exposure to Cd. Male ICR mice received CdCl2 (100 mg/L) via drinking water for 8 weeks. After Cd exposure, DMSA at a dose of 25 mg/kg or 50 mg/kg was intragastrically administered once daily for 5 consecutive days at the end of Cd treatment. It was found that Cd-induced hypertension and markedly blunted vascular responses to vasoactive agents, including acetylcholine, phenylephrine and sodium nitroprusside. Treatment with DMSA significantly restored blood pressure and improved vascular responsiveness when compared with Cd-treated controls. Moreover, DMSA protected against Cd-induced severe oxidative stress by normalization of the redox ratios of glutathione to glutathione disulfide and suppression of plasma malondialdehyde, plasma protein carbonyl, urinary nitrate/nitrite, and superoxide production from thoracic aorta. DMSA partially reduced Cd contents in the blood, heart, liver and kidneys. In conclusion, our present study provides the first evidence of the therapeutic efficacy of DMSA against oxidative stress and vascular dysfunction in Cd-intoxicated mice.

Gallium arsenide (GaAs), an inter-metallic semiconductor, known to exhibit superior optical and electronic properties compared to silicon, promotes its use in semiconductor industries. Extensive use of GaAs will inevitably lead to an increase in the exposure of workers manufacturing these products. Antioxidants are exogenous or endogenous compounds acting in several ways, including scavenging reactive oxygen species (ROS) or their precursors, inhibiting ROS formation, and binding metal ions needed for the catalysis of ROS generation. In the present study we investigated the protective efficacy of α-lipoic acid, quercetin and captopril individually against gallium arsenide exposure. Co-administration of α-lipoic acid with GaAs was most effective in reducing GaAs induced inhibition of blood δ-aminolevulinic acid dehydratase (ALAD) activity, liver, kidney and brain reduced glutathione (GSH) level and elevation of oxidized glutathione (GSSG). Captopril, on the other hand was effective in reducing thiobarbituric acid reactive substance (TBARS) levels, while quercetin reduced ROS in liver and kidney. The results suggest comparatively better preventive efficacy of concomitant α-lipoic acid administration during Gallium arsenide exposure compared to quercetin and captopril in preventing GaAs induced oxidative stress.

Fluoride is a ubiquitous environmental pollutant. In the current study we have investigated the antioxidative properties of an ethanol extract of the bark of Terminalia arjuna (T. arjuna ethanol extract [TAEE]) against sodium fluoride (NaF)-induced oxidative stress in murine heart. Experimental mice were divided into four groups. The first group served as the normal control. The second group received NaF at a dose of 600 ppm through drinking water for 1 week and served as the toxin control. The third group was exposed to TAEE (at a dose of 50 mg/kg of body weight for 1 week) prior to NaF intoxication, and the last group was treated with vitamin C at a dose of 100 mg/kg body weight for 1 week prior to NaF intoxication and served as the positive control in the study. The activities of various antioxidant enzymes (superoxide dismutase, catalase, and glutathione S-transferase), levels of cellular metabolites, reduced glutathione, and oxidized glutathione, levels of lipid peroxidation end products, and protein carbonyl contents were determined in the cardiac tissues of all the experimental animals. NaF intoxication significantly altered all the indices related to the prooxidant-antioxidant status of the heart; treatment with the active constituents prior to NaF administration, however, prevented these alterations. In addition, the ferric reducing/antioxidant power assay revealed that TAEE enhanced the cardiac intracellular antioxidant activity. Histological studies also demonstrated a cardioprotective action of TAEE. The combined results suggest that TAEE protects murine hearts from NaF-induced oxidative stress, probably via its antioxidant properties.

D-Galactosamine (GalN)-induced liver injury is associated with reactive oxygen species and oxidative stress. In the present study, we evaluated the effect of alpha lipoic acid (ALA) supplementation on acute GalN-induced oxidative liver injury. Hepatotoxicity induced by single intraperitoneal injection of GalN (500 mg/kg body wt) was evident from increase in lipid peroxidation and serum marker enzymes (asparate transaminase, alanine transaminase, alkaline phosphatase, and lactate dehydrogenase). The decreased activities of enzymic antioxidants (superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase) as well as glutathione levels were the salient features observed in GalN-induced hepatotoxicity. Pretreatment with ALA (50 mg/kg body weight for 7 days) significantly precluded these changes and prevents the hepatic injury. Hence, this study clearly exemplified that ALA might be a suitable candidate against GalN-induced cellular abnormalities.

Arsenic is highly toxic naturally occurring element that affects numerous organ systems in humans. Present study was designed to investigate the preventive role of a triterpenoid saponin, arjunolic acid (AA) against arsenic-induced nephrotoxicity in mouse model. For this study, NaAsO(2) was chosen as the source of arsenic. Oral administration of NaAsO(2) at a dose of 10mg/kg body weight for 2 days caused significant accumulation of arsenic in renal tissues as well as altered the activities of serum markers, urea nitrogen (UN) and creatinine, antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), glutathione reductase (GR) and glutathione peroxidase (GPx), level of cellular metabolites, reduced glutathione (GSH), oxidized glutathione (GSSG) and total thiols, level of lipid peroxidation end products and protein carbonyl content. Treatment with AA at a dose of 20mg/kg body weight for 4 days almost normalized above indices. Histological studies also indicated preventive role of AA against NaAsO(2)-induced nephrotoxicity. The radical scavenging activity and in vivo antioxidant power of AA were determined from its DPPH radical scavenging ability and ferric reducing/antioxidant power (FRAP), respectively. A well-known antioxidant, vitamin C was used as positive control throughout the study. Combining all, results suggest that arsenic could cause kidney damage by inducing oxidative stress in mice and that could be prevented by AA.

We studied the efficacy of quercetin and a thiol chelating agent, monoisoamyl 2, 3-dimercaptosuccinic acid (MiADMSA) either individually or in combination against arsenic-induced oxidative stress and mobilization of metal in mouse. Animals were chronically exposed to 25 ppm arsenite as sodium arsenite in drinking water for 12 months followed by treatment with MiADMSA (0.2 mmol/kg, orally), quercetin (0.2 mmol, orally) either alone or in combination, once daily for 5 consecutive days. Arsenic exposure led to a significant depletion of blood delta-aminolevulinic acid dehydratase (ALAD) activity, glutathione, white (WBC) and red blood cell (RBC) counts, and an increase in platelet levels while significantly increasing the level of reactive oxygen species (in RBCs). Hepatic reduced catalase (CAT) and glutathione peroxidase activities showed a depletion, whereas thiobarbituric acid reactive substances (TBARS) levels increased on arsenic exposure indicating arsenite-induced oxidative stress in blood and liver. Kidney CAT activity showed a depletion, whereas TBARS levels increased on arsenic exposure. These biochemical changes were accompanied by an increase in blood, liver, and kidney arsenic concentration. Treatment with MiADMSA was effective in increasing ALAD activity, whereas quercetin was ineffective when given alone. Quercetin when co-administered with MiADMSA also provided no additional beneficial effect on blood ALAD activity but significantly brought altered platelet counts nearer to the normal value. In contrast, administration of quercetin alone provided significant beneficial effects on hepatic oxidative stress and kidney TBARS levels. Renal biochemical variables remained insensitive to arsenic and any of the treatments. Interestingly, combined administration of quercetin with MiADMSA had a remarkable effect in depleting total arsenic concentration from blood and soft tissues. These results lead us to conclude that quercetin administration during chelation treatment had some beneficial effects particularly on the protection of inhibited blood ALAD activity and depletion of arsenic level from target organs. The study supports our earlier conclusion that a co-administration of an antioxidant particularly flavonoids more beneficial than monotherapy with the chelating agents to achieve optimal effects of chelation in arsenite toxicity.

Arsenic, a notoriously poisonous metalloid, is ubiquitous in the environment, and it affects nearly all organ systems of animals including humans. The present study was designed to investigate the preventive role of a triterpenoid saponin, arjunolic acid against arsenic-induced oxidative damage in murine brain. Sodium arsenite was selected as a source of arsenic for this study. The free-radical-scavenging activity and the in vivo antioxidant power of arjunolic acid were determined from its 2,2-diphenyl-1-picryl hydrazyl radical scavenging ability and ferric reducing/antioxidant power assay, respectively. Oral administration of sodium arsenite at a dose of 10 mg/kg body weight for 2 days significantly decreased the activities of antioxidant enzymes, superoxide dismutase, catalase, glutathione-S-transferase, glutathione reductase and glutathione peroxidase, the level of cellular metabolites, reduced glutathione, total thiols and increased the level of oxidized glutathione. In addition, it enhanced the levels of lipid peroxidation end products and protein carbonyl content. Treatment with arjunolic acid at a dose of 20 mg/kg body weight for 4 days prior to arsenic administration almost normalized above indices. Histological findings due to arsenic intoxication and arjunolic acid treatment supported the other biochemical changes in murine brains. Results of 2,2-diphenyl-1-picryl hydrazyl radical scavenging and ferric reducing/antioxidant power assays clearly showed the in vitro radical scavenging as well as the in vivo antioxidant power of arjunolic acid, respectively. The effect of a well-established antioxidant, vitamin C, has been included in the study as a positive control. Combining all, results suggest that arjunolic acid possessed the ability to ameliorate arsenic-induced oxidative insult in murine brain and is probably due to its antioxidant activity.

Arsenic-induced tissue damage is a major concern to the human population. An impaired antioxidant defense mechanism followed by oxidative stress is the major cause of arsenic-induced toxicity, which can lead to reproductive failure. The present study was carried out to investigate the preventive role of arjunolic acid, a triterpenoid saponin isolated from the bark of Terminalia arjuna, against arsenic-induced testicular damage in mice. Administration of arsenic (in the form of sodium arsenite, NaAsO(2), at a dose of 10 mg/kg body weight) for 2 days significantly decreased the intracellular antioxidant power, the activities of the antioxidant enzymes, as well as the levels of cellular metabolites. In addition, arsenic intoxication enhanced testicular arsenic content, lipid peroxidation, protein carbonylation and the level of glutathione disulfide (GSSG). Exposure to arsenic also caused significant degeneration of the seminiferous tubules with necrosis and defoliation of spermatocytes. Pretreatment with arjunolic acid at a dose of 20 mg/kg body weight for 4 days could prevent the arsenic-induced testicular oxidative stress and injury to the histological structures of the testes. Arjunolic acid had free radical scavenging activity in a cell-free system and antioxidant power in vivo. In summary, the results suggest that the chemopreventive role of arjunolic acid against arsenic-induced testicular toxicity may be due to its intrinsic antioxidant property.

Co-administration of iron in combination with monoisoamyl dimercaptosuccinic acid (MiADMSA) against chronic arsenic poisoning in mice was studied. Mice preexposed to arsenic (25 ppm in drinking water for 6 months) mice were treated with MiADMSA (50 mg/kg, intraperitoneally) either alone or in combination with iron (75 or 150 mg/kg, orally) once daily for 5 days. Arsenic exposure led to a significant depletion of blood delta-aminolevulinic acid dehydratase (ALAD) activity, hematocrit, and white blood cell (WBC) counts accompanied by small decline in blood hemoglobin level. Hepatic reduced glutathione (GSH) level, catalase and superoxide dismutase (SOD) activities showed a significant decrease while, oxidized glutathione (GSSG) and thiobarbituric acid-reactive substances (TBARS) levels increased on arsenic exposure, indicating arsenic-induced hepatic oxidative stress. Liver aspartate and alanine transaminases (AST and ALT) activities also decreased significantly on arsenic exposure. Kidney GSH, GSSG, catalase level and SOD activities remained unchanged, while, TBARS level increased significantly following arsenic exposure. Brain GSH, glutathione peroxidase (GPx), and SOD activities decreased, accompanied by a significant elevation of TBARS level after chronic arsenic exposure. Treatment with MiADMSA was marginally effective in reducing ALAD activity, while administration of iron was ineffective when given alone. Iron when co-administered with MiADMSA restored blood ALAD activity. Administration of iron alone had no beneficial effects on hepatic oxidative stress, while in combination with MiADMSA it produced significant decline in hepatic TBARS level compared to the individual effect of MiADMSA. Renal biochemical variables were insensitive to any of the treatments. Combined administration of iron with MiADMSA also had no additional beneficial effect over the individual protective effect of MiADMSA on brain oxidative stress. Interestingly, combined administration of iron with MiADMSA provided more pronounced depletion of blood arsenic, while no additional beneficial effects on tissue arsenic level over the individual effect of MiADMSA were noted. The results lead us to conclude that iron supplementation during chelation has some beneficial effects particularly on heme synthesis pathway and blood arsenic concentration.

We compared the therapeutic efficacy of captopril and a thiol chelating agent, meso 2,3-dimercaptosuccinic acid (DMSA) either individually or in combination against arsenite induced oxidative stress and mobilization of metal in rats. Animals were exposed to 100 ppm arsenite as sodium arsenite in drinking water for six weeks followed by treatment with DMSA (50 mg/kg, orally), captopril (50 mg/kg, intraperitoneally) either alone or in combination, once daily for 5 consecutive days. Arsenite exposure led to a significant depletion of blood delta-aminolevulinic acid dehydratase (ALAD) activity, glutathione and platelet levels while significantly increased the level of reactive oxygen species (in RBCs). Hepatic reduced glutathione (GSH) level showed a significant decrease while, thiobarbituric acid reactive substances (TBARS) levels increased on arsenite exposure indicating arsenite induced hepatic oxidative stress. Kidney GSH, GSSG, catalase and TBARS remained unchanged on arsenite exposure. Treatment with DMSA was effective in increasing ALAD activity while, captopril was ineffective when given alone. Captopril when co-administered with DMSA also provided no additional beneficial effect on blood ALAD activity but significant brought altered platelet counts back to the normal value. In contrast, administration of captopril alone provided significant beneficial effects on hepatic oxidative stress, and in combination with DMSA provided a more pronounced recovery in the TBARS level compared to the individual effect of DMSA and captopril. Renal biochemical variables remained insensitive to arsenite and any of the treatments. Interestingly, combined administration of captopril with DMSA had a remarkable effect in depleting total arsenic concentration from blood and soft tissues. These results lead us to conclude that captopril administration during chelation treatment had some beneficial effects particularly on the protection of inhibited blood ALAD activity, and depletion of arsenic level. The study supports our earlier conclusion that a co-administration of an antioxidant is more beneficial than monotherapy with the chelating agents, in order to achieve optimal effects of chelation in arsenite toxicity.

Teratogenesis has been a topic of increasing interest and concern in recent years, generating controversy in association with danger to humans and other living things. A veritable host of chemicals is known to be involved, encompassing a wide variety of classes, both organic and inorganic. Contact with these chemicals is virtually unavoidable due to contamination of air, water, ground, food, beverages, and household items, as well as exposure to medicinals. The resulting adverse effects on reproduction are numerous. There is uncertainty regarding the mode of action of these chemicals, although various theories have been advanced, e.g., disruption of the central nervous system (CNS), DNA attack, enzyme inhibition, interference with hormonal action, and insult to membranes, proteins, and mitochondria. This review provides extensive evidence for involvement of oxidative stress (OS) and electron transfer (ET) as a unifying theme. Successful application of the mechanistic approach is made to all of the main classes of toxins, in addition to large numbers of miscellaneous types. We believe it is not coincidental that the vast majority of these substances incorporate ET functionalities (quinone, metal complex, ArNO2, or conjugated iminium) either per se or in metabolites, potentially giving rise to reactive oxygen species (ROS) by redox cycling. Some categories, e.g., peroxides and radiation, appear to generate ROS by non-ET routes. Other mechanisms are briefly addressed; a multifaceted approach to mode of action appears to be the most logical. Our framework should increase understanding and contribute to preventative measures, such as use of antioxidants.